Did FDA's Vytorin warning negatively impact health outcomes?

A new study found a substantial uptick in nonadherence rates in the months after the FDA issued a caution about Merck/Schering-Plough's ezetimibe. The agency's handling of the debacle, researchers say, points to a need for better public-health warnings about medications.

Researchers keyed in on an FDA communication to clinicians issued January 25, 2008, regarding ezetimibe (known as either Zetia or the ezetimibe-simvastatin combination, Vytorin). MSP had just released long-delayed and disappointing data from the ENHANCE trial, which found no advantage for Vytorin over simvastatin in slowing the progress of atherosclerosis.

The agency raised questions about the effectiveness of the drug but did not advise healthcare professionals to discontinue prescribing it. Following the memo, and as media attention on the drug's effectiveness kicked into high gear, adherence rates among patients fell 5.7%.

Among those patients who discontinued ezetimibe after the FDA warning, 16.5% switched to another clinically appropriate therapy, according to findings, which are based on a review of de-identified claims data for more than 860,000 patients identified as new users of the drug between January 2006 and August 2008. (Discontinuation rates were tracked for six months after the FDA communication.)

Findings indicate a “substantial increase” in ezetimibe nonpersistence rates and a “small proportion” of patients making a clinically appropriate switch after discontinuation, researchers concluded in the paper, published in this month's issue of the journal Medical Care.

Because the FDA's 2008 communication was not related to a safety issue or accompanied by clear guidelines about how to apply the information, confusion reigned, the kind that “can bluntly reduce overall rates of treatment,” said study co-author Niteesh Choudhry, MD, PhD, in a statement.

Furthermore, if patients stop therapy altogether without switching to another medication, “there could be a negative impact on health outcomes,” added Choudhry, who is with Brigham and Women's Hospital. He and fellow researchers from Harvard University and CVS Caremark, whose study was part of a collaboration designed to come up with solutions to the nonadherence problem, called for more effective public-health warnings regarding new data about medications.

Merck, which now sells Vytorin and ezetimibe on its own (under the brand Zetia), has seen sales of the drugs tank 45% since the ENHANCE results came out. The company is waiting for results of the IMPROVE-IT trial, scheduled for completion in 2013, to provide cardiovascular outcomes data for Vytorin vs. simvastatin alone in patients with acute coronary syndrome. That could partially vindicate Vytorin, and help Merck compete against cheap generic versions of off-patent cholesterol-lowering statins Zocor (simvastatin) and Lipitor (atorvastatin).

A number of previous studies have demonstrated that FDA warnings about the safety or efficacy of drugs lead to reduced rates of physician prescribing and patient medication use. But the communication issued about ezetimibe was somewhat unusual, in that there was no clear signal of harm detected. The signal from ENHANCE indicated lack of efficacy on a pre-specified outcome, coronary intimal wall thickness.

Indeed, In January 2009, when the FDA announced that it had completed its review of ENHANCE, the agency stated that the results did not change its position that elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease.

The authors caution against assuming that the associations between the FDA warning and the rise in patient nonpersistence are causal. Other factors may have contributed.

In an accompanying article by Gerald Dal Pan, MD, of the FDA's Center for Drug Evaluation and Research, he addresses some of the issues that Choudhry and colleagues bring up on how FDA communicates with the public. “Communicating the risks of drugs and assessing the impact of those communications are complicated endeavors,” acknowledges Dal Pan.

Many issues are widely publicized either before or shortly after a specific FDA warning. “Indeed,” writes Dal Pan, "publicity itself may have both affected the response to the warning and also provided the impetus to study the impact of the warning.”

That was certainly the case in the aftermath of ENHANCE, when patients and physicians may have learned about ezetimibe's efficacy questions from a medical journal, media coverage, or responses from clinicians and specialty societies. Researchers were unable to isolate the effects of any particular message.

Nevertheless, they write, “as the nation's regulatory agency for prescription medications, the FDA is expected to play a meaningful role in educating physicians and patients about issues related to the safety and efficacy of medications they regulate and should take some responsibility in helping patients and physicians to interpret new information about a medication's safety and/or efficacy.”

Not everyone agrees with that suggestion. Dictating medical practice "is not the job of the FDA," said cardiologist Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation. "That's a job for guideline writers and professional societies. The job of the FDA is to be neutral on these medical practice issues. And to in fact tell people what they know and what they don't know, but not tell them how to practice medicine."

Nissen made several media appearances in 2008 advising that Zetia and Vytorin should both be relegated to last-resort status. Asked whether he thinks the FDA's warning may have negatively impacted health outcomes, he told MM&M, "Absolutely not. And in fact, who said that people stopping ezetimibe is bad for health outcomes? We don't know yet whether the drug is favorable or unfavorable. So the implication that somehow putting a warning out about the drug is bad for health outcomes doesn't make any sense."

He added, "Many of us believe that the drug was being used inappropriately, and a better choice for these patients would have been a statin. In fact, at the time that this warning came out, there was data to suggest that the usage pattern of ezetimibe in the United States was fivefold greater than it was in Canada, where there's not direct-to-consumer advertising and where their tendency is to practice evidenced-based medicine. So the suggestion that there was somehow a health harm in putting out the warning is illogical."